Current Understanding of the Transmission, Diagnosis, and Treatment of H. pylori Infection: A Compre

International Journal of Medical, Pharmacy and Drug Research (IJMPD)

Article DOI: https://dx.doi.org/10.22161/ijmpd.7.2.1

Peer-ReviewedJournal Int.J.Med.Phar. DrugRe.,7(2),2023

ISSN: 2456-8015

Current Understanding of the Transmission, Diagnosis, and Treatment of H. pylori Infection: A Comprehensive Review

Hend Sadeq Mohammed Aljaberi1

, Nida Khalid Ansari1 , Mengqiu

Xiong

1 , Hongxin Peng1 , Bangshun He *,1,2 and Shukui Wang*,1,2

1Department of Laboratory Medicine, Nanjing First Hospital, Nanjing Medical University, China

2H.pylori Research Key Laboratory, Nanjing Medical University, Nanjing, China

Received: 11 Feb 2023; Received in revised form: 14 Mar 2023; Accepted: 21 Mar 2023; Available online: 28 Mar 2023

©2023 The Author(s). Published by AI Publications. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/)

Abstract

H. pylori infection is a prevalent bacterial infection that affects the gastric mucosa of humans, with a prevalence ranging from 30% to 90%, depending on the region. The infection is a significant cause of gastritis, peptic ulcer disease, and gastric cancer. In this comprehensive review, we discuss the current understanding of the transmission, diagnosis, and treatment of H. pylori infection. We describe the risk factors and epidemiology of the infection, along with its pathogenesis, which involves multiple virulence factors that contribute to the colonization and survival of the bacteria in the acidic stomach environment. Diagnostic tests for H. pylori infection include invasive and non-invasive methods, with the choice of test depending on several factors. Treatment of H. pylori infection is aimed at eradicating the bacteria and preventing complications. Antibiotic-based triple or quadruple therapy, in combination with acidsuppressing agents, is the standard treatment, but antibiotic resistance is an emerging problem that needs to be addressed. This comprehensive review provides a useful resource for clinicians, researchers, and public health officials involved in managing H. pylori infection and its associated complications.

Keywords Diagnostic, and Treatment, Epidemiology of H. pylori, H. pylori, Risk factors, Pathogenesis.

I. OVERVIEW

H. pylori is a helical-shaped, microaerophilic, and Gram-negative bacterium with a unipolar flagella bundle (Figure 1 ) [1].which was first diagnosed in gastric mucosa of patients suffering from gastritis and peptic ulcer, it was then successfully cultured by the two Australian doctors; Barry J Marshall and Robin Warren, [2]. Noticeably, this discovery contradicted the previously held scientific belief that the stomach is a germ-free organ, and this discovery resulted intheaward.

of the Noble prize 2005 to Marshall and Warren in Physiology and Medicine. Chronic infection of H. pylori in humans is prevalent in more than half of the world’s population [3]. Furthermore, H. pylori may also be associated with gastric mucosaassociated lymphoid tissue lymphoma, one of the most prevalent extranidal non-Hodgkin lymphomas [4]. There is evidence that this neoplasm is caused by chronic gastritis caused by H. pylori. There is no specific clinical presentation of this disease, which can range from dyspepsia to the classic B-symptoms associated withother lymphomas

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Aljaberi etal./CurrentUnderstanding oftheTransmission,Diagnosis,andTreatment of H.pyloriInfection: A ComprehensiveReview

Acute complications may also occur, including intestinal obstruction, perforation, and hemorrhaging [5]. However, only a few infected people are prone to develop serious clinical symptoms of H. pylori infection, which in turn is determined by several factors which particularly depend on the host's immune status, such as the presence of particular receptors and the efficiency of inflammatory responses. Clinical outcome of H. pylori infection also depends on factors in the environment and strain specificity that influence the pathogenicity of the strains(straindiversity) [6]

and Type 3 has a tightly coiled structure and lacks periplasmicfibers.

Generally, stomach Helicobacter species isolated from animals other than cats and dogs exhibit distinct and sometimes similar morphology to H. pylori. On the basis of 16s rRNA similarity, a phylogenetic analysis of contemporary gastric, enteric, and hepatobiliary Helicobacter species has beenconducted. [8]

Table 1 Human and land animal gastric Helicobacter [8]

TAXONOMY NATURAL HOST

H. acinonychis Cheetah

H. bizzeroni Dog

Candidatus Helicobacter bovis Cattle

H. felis Cat

H. heilmannii Human, non-human primate,pigs

Candidatus Helicobacter

suis Pig

H. mustelae Ferret

H. nemestrinae Macaque

1.1 Taxonomy of H. pylori

H pylori has a helix-shaped shape (hence its name) and to colonize the stomach, it can physically screw itself into the lining Scientific classification of the bacteria is:

Kingdom:Bacteria

Phylum:Proteobacteria

Class:EpsilonProteobacteria

Order:Campylobacterales

Family:Helicobacteraceae

Genus:Helicobacter

Species: H. pylori [7]

1.2 Gastric helicobacter species

To present, nine Helicobacter species capable of hydrolyzing urea have been cultured from the stomachs of humans and land animals (Table 1). [8] The Lockard classification system divides these into three types: Type 1 has a tapered end and a fusiform to slightly spiral shape; Type 2 has sparsely distributed periplasmic fibers and can be seen singly or in groups of two to four, and has a spiral shape;

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H. pylori Human, monkey,sheep

H. salomonis Dog

H. suncus Shrew

II. TRANSMISSION OF H. PYLORI INFECTION

The precise mode of route of H. pylori infection transmission unproven. The H. pylori can spread either directly from person to another or indirectly from an infected person to the environment, according to studies [9]. The human stomach is the most significant reservoir of H. pylori, and it is possible for pass from the stomach to the external environment via feces, vomitus, or gastric regurgitation [10].Currently, interpersonal transmission is more likely than environmental transmission. Transmission from person to person can be primarily fecal-oral or oral-oral. In the last 30 years, it has been reported in numerous articles that there are several potential sources and vectors of H. pylori infections, as well as risk factors related to both fecal-oral and oral-oral transmission routes, and

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Fig 1 H. pylori; Under a scanning electron microscope (left), with its unipolar flagella is shown in a schematic (right).[1]

exposure to contaminated food, water, and animals. They tried isolating H. pylori from feces, saliva, and dentalplaque [9]

2.1 Gastro-oral routes

H. pylori is acquired during infancy and transmission may occur through the vomiting of achlorhydric mucus Transmission may occur through the gastric juices, particularly as a result of vomiting in childhood [11] Studies reported percentages of H. pylori isolated from the gastric juice of symptomatic patients: A high concentration of the microorganism is frequently found in vomit, where it appears to survive outside of the human body in unbuffered gastric juice The results of these studies support the hypothesis that gastro-oral transmission occurs in unsanitary conditions, particularly during childhood [12]

2.2 Oral-oral route

Despite the possibility that the human oral cavity may serve as a source of H. pylori infection, It is not certain whether the oral cavity can function as a lastingreservoirforthemicroorganism,orifitis only occasionally detected due to gastroesophageal reflux or vomiting in the saliva or on the oral mucosa [13] One might be first address if oral and gastric H. pylori carriage are associated. A number of studies have reported a relation between oral and gastric H. pylori [14] Saliva has been found to directly culture H. pylori, and the DNA from both subgingival biofilm and dental plaque has been amplified on numerous occasions [15]. Oral-oral transmission involves infants can be infected with H. pylori directly from their mothers through their oral secretions. Discordance of strain types between mother and child is one of the negative arguments against oraloral transmission [16], Although this is debatable, other reports indicate the presence of common strainsthatinfectcouples[17].

2.3 Fecal-Oral Transmission

DNA of H .pylori has been frequently detected in human feces, but there has been limited success in cultivating H. pylori from feces because this organism persists in a non-cultivable form (coccoid) [10]. Many studies have established the relation between the seroprevalence of hepatitis A virus and H. pylori, suggesting similar (fecal-oral) mode of transmission for both pathogens [18]. In addition, H. pylori has

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been detected and cultured in samples of drinking water. Consequently, the public water system has been identified as a potential source of H. pylori infection[19]

2.4 Contaminated water sources and food

Based on the analysis of the genome, it has been determined that H. pylori is unlikely to multiply in the environment When kept refrigerated, H. pylori can remain viable in water, milk, and a range of foods for several days. This suggests that water or food that is contaminated with H. pylori could pose a risk of infection for humans [10]. In water, at 20–230 C, H. pylori could be cultured for up to 24 hours, while at 160 C, it might to 3 days [20] Among Lima children living in low and high socioeconomic status families, municipal water supply appears to be a significant source of infection [21] A mode of transmission of H. pylori has also been described through the consumption of raw vegetables [22], also reported that the infection was more prevalent in children who regularly consumed raw vegetables andwhoswam inriversandpools orusedstreamsas a source of drinking water [23] Milk, meat, and vegetables are among the food products analyzed Milk products have been the subject of the most research, likely due to the fact that the infection is typically acquired during childhood, when milk consumptionisprevalent [24]

2.5 Animal reservoirs

There is a possibility of zoonotic transmission of H. pylori from non-primate reservoirs, but this transmission has not been demonstrated [25]. In1990.strain of the bacteria was isolated from the stomach of a pig, suggesting that pigs could serve as a reservoir for this bacterium [26]. The hypothesis was supported by other studies; by successfully infecting pigs, specimens that subsequently developedgastroenteritis were obtained [27].

A second study identified H pylori in six cats using 16S rDNA sequencing [28]. However, no other studies confirm these results. Further studies are needed to determine whether cats are an important route of transmission for H. pylori According to the available data, owners of cats are not at risk of contracting H. pylori fromtheirpets

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2.6 Interfamilial transmission

There is a higher prevalence of H. pylori infection among children whose parents are infected than among children whose parents are uninfected. Molecular studies have demonstrated that family members frequently share the same H. pylori strain.[10]. It is likely that the infection transmitted from one member of the family to another within the family or contracted from an environmental source withinthefamily.

The spread of the infection appears to be facilitated by close intrapersonal contact: childhood overcrowding has been repeatedly identified as a significant risk factor for the development of H pylori infection Infection in both children and adults, supporting the person-to-person transmission theory [29] In developing countries, with large families and numerous siblings, sibling-sibling transmission may be more significant [30], whereas in developed countries, the average number of children per family is low, mothers may play a crucial role [31] The majority of studies have not found fathers who are positive for H. pylori to be significant risk factors for their children's infection [32]. Child-to-adult transmission appears to be improbable. A nine-year follow-up study of 46 families in Japan revealed no cases of transmission from an infected child to an uninfected parent [33] There was no higher likelihood of H. pylori infection observed among children who attended day care centers in Sweden, compared to those who received care exclusively at home [10].

III. RISK FACTORS FOR INFECTION

Exposure to the bacterium is a necessary condition for the development of infection. It is dependent on the characteristics of the infectious source and the contact that results in exposure, but the infection and persistence are also influenced by the host and the bacterium The successful establishment of an infection in a new individual, the bacterium must overcome numerous obstacles [34]

Exitfromaninfected individual, Surviving outsidethegastricniche, Newhostintroduction, Gastricmucosa colonization,and;

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Colonizationmaintenance.

Predominant person-to-person transmission is hypothesized. This theory is based on the fact that the infection tends to cluster within families [32] and in institutionalized individuals in the absence of consistent and verifiable environmental reservoirs [35]

3.1 The family

Transmission of H. pylori primarily occurs within the family context, with a child's likelihood of infection being linked to the presence of infected family members [32] It is often suggested that family size and residential crowding (persons per room or m2) are risk factors for H .pylori infection and may be considered indicators of the number of infected members in a family [36] Similarly, children living in low-prevalence regions are more likely to become infected if their families are connected to highprevalence areas, and these effects diminish with each successive generation [37]. Infection in adulthood can be predicted by the living conditions during childhood in relation to acquiring H. pylori from household members during childhood [38]. The prevalence of mother-to-child transmission suggests that having an infected mother is a more significant risk factor for childhood infection than having an infected father. The clustering of the infection on sib ships has also been interpreted as evidence of transmission among siblings. [32]. Although H. pylori infection is usually contracted during early childhood, certain epidemiological evidence suggests that it could be transmitted within families during adulthood as well. Having a spouse who is infected has been identified as a risk factor for infection [39] In addition, the risk of infection in adults has been associated with having a greater number of children, indicating that children may play a role as transmission mediators withinfamilies [40]

3.2 Environmental and behavioral factors

Environmental and behavioral factors related to low socioeconomic status have been investigated in relation to H. pylori infection Theoretically, the observed clustering of H. pylori infection within families may be due to a common environmental source of the infection. Since the use of certain water sources, like wells, has been correlated with the

infection, it has been suggested that contaminated watermaybethesource [41]

However, other studies have not found an association between the water source and infection [23]. Furthermore, it has been suggested that H. pylori have zoonotic potential, with reservoirs including houseflies, cats, , and sheep, but these theories have been contested [34] Behavior factors may influence H. pylori acquisition and persistence. Living in a high-prevalence nation can facilitate infection, as increasing bacterial exposure is possible due to regular and close interaction with individuals who are infected, as well as inadequate hygiene practices [41]. Intimate contact has also been proposed as an explanation for other observed risk factors, including bedsharing and breastfeeding. It has also been hypothesized that breastfeeding may provide protection against early infection through passive immunization. These results suggest that such protection, if present, is of limited importance after weaning [30]. Moreover, consumption of antibiotics has been shown to negatively correlate with H. pylori infection [34]. In a different study, a comparable negative correlation was no longer observed once the country of origin was taken into account, potentially because low-prevalence countries have a higher rate of antibiotic usage [38]. Several behavioral factors have been identified as factors that influence the likelihood of H. pylori infection in adults. Among the examples are possible negative associations with alcohol consumption [42], and possibly a positive relationship with smoking, although data are contradictory [38]

3.3 Host and bacterial factors

The ability of H. pylori strains to initiate and maintain an infection in a specific host can be influenced by various factors, including both the host and bacterial characteristics, as well as their compatibility with one another [43] During childhood, transient infections may occur when the bacteria are not optimally suited for the new host and adaptation is not feasible or quick enough, resulting in the infection being cleared by the host [44] Based on the fact that there is a higher agreement of infection between monozygotic twins (81%) compared to dizygotic twins (63%), it has been proposed that a person's genetic makeup plays a role in their susceptibility to H. pylori infection However, there are certain host factors that

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may be linked to an increased susceptibility to infection, though the particular genetic elements of this predisposition remain unknown. It has been suggested that the expression of blood group antigens that mediate bacterial adhesion to the gastric mucosa is crucial for susceptibility to H. pylori infection[34]

The binding affinities of H. pylori strains have been shown to be adapted according to the expression of blood group antigens in various human populations, according to some research [45]. Moreover, individuals who release receptors into their bodily fluids, which can act as detachable binding sites that compete with tissue-bound receptors, have been found to have a reduced risk of infection [46] However, studies have raised questions about the hypothesis that adhesion mediated by blood group antigens plays a role in determining susceptibility to infection [47]. The susceptibility to H. pylori infection may also be influenced by the immune system. This notion is supported by studies demonstrating that alleles within the HLA-DQA1 human leukocyte antigen locus are associated with infection. [48]. The infection has also been correlated with a polymorphism in the interleukin (IL)-1 receptor of unknownfunctionalsignificance [49].

Furthermore, low gastric acid secretion may promote the spread of the bacterium, this may be particularly important in young children and in cases of infectious gastroenteritis [50]. Some studies have found slightly higher in infection among males [38] This tendency's causes are unknown, and other studies have been unable to confirm this correlation [44] H pylori has evolved a range of mechanisms for survival in harsh gastric niches, which include the ability to tolerate acid, to move, to adhere, to evade immune system detection, and to adapt to the environment. These traits play a role in the interplay between the host and the bacteria and can affect the acquisition and longevity of infection in animal models. The first factors implicated in colonization were acid tolerance and motility of bacteria [34]

These findings have been validated by global mutagenesis techniques, which have also increased the number of putative essential genes [51] However, it is unclear how relevant these findings are to human populations. In a Finnish population, it has been shown that strains with the cag

pathogenicity island (PAI), a virulence factor, disappear more rapidly than strains without the cag PA [52] The reduction in transmissibility or persistence of cag PAI strains in this population might explain this phenomenon. however, the majorityofinfectionin worldwideiscagPAI+ [53]

IV. EPIDEMIOLOGY OF H. PYLORI INFECTION

4.1 Prevalence and geographical distribution

H. pylori is the most prevalent human infection worldwide, colonizing over fifty percent of the world's population with a wide variation in its geographical distribution. Africa has the highest prevalence of H. pylori at approximately 79.1%, while Northern America and Oceania have the lowest at 24.4%. [3] (Figure 3). Rural areas have a higher prevalence of the disease than urban areas reflects differences in sanitation, socioeconomic status, urbanization, and access to clean water [54] Interestingly, the prevalence of H. pylori varies between populations even in the same country. Moreover, H. pylori prevalence varies between different ethnic groups residing in the same country. For instance, The prevalence of H. pylori infection varies between non-white and non-Hispanic white populations in the United States, with a range of 34.5% to 61.6% among non-whites and 18.4% to 26.6% among non-Hispanic whites[55]. Similarly, Malaysian population comprise of Malay, Chinese and Indians ethnic groups, the H. pylori prevalence in Malay is (19.9%), Indians (50.7%) and Chinese (40%) [56]. WHO has identified H. pylori as a Group I carcinogen responsible for the development of gastric adenocarcinoma. Infection with H. pylori is responsible for nearly 89 % of gastric cancer cases [57]. Previously, in China, complete eradication of H. pylori infection has been shown to reduce gastric cancer incidences from 25% to 16.67%. [58]. In developed countries such as Canada, the United States, and Northern Europe, the prevalence of H. pylori is low and infection rates remain constant compared to Africa, Latin America, India, and Eastern Europe. This may be a result of enhanced hygiene, sanitation, and the active elimination of carrier state by antimicrobial therapies [59] Furthermore, H. pylori shows high prevalence rates of

58 to 62% in India in patients with dyspeptic symptoms[60]

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4.2 Incidence of H. pylori infection

Comparatively, the annual incidence of H. pylori infection in industrialized countries is approximately 0.5%, compared to 4%–15% in developing countries [61] Living in an underdeveloped nation and possessing a low economic status are welldocumented factors that increase the likelihood of being at risk [62]. Retrospective longitudinal sero surveys conducted primarily in industrialized countries are the main source for incidence rates in adults. Seroconversion (i.e., change in serostatus from seronegative to seropositive) generally occurs at a rate of less than 1% per year of follow-up, indicating that adult infection appears to be a rare occurrence. Seroreversion appears to occur at a similar or higher frequency than seroconversion [10]. Few data exist regarding the prevalence of infection between adults in developing countries. During 56 months of follow-up in Brazil, every year, a 1.1% rate of seroconversion and a 0.2% rate of seroreversion were observed [63]. In low-income countries, early childhood incidence rates above 20% per year have beenreported [34].

V. CLINICAL MANIFESTATIONS OF H. PYLORI INFECTION

Over 50% of the population of the world is infected with H. pylori and causes histologic gastritis in all patients; however, only 10 to 20 percent of infected individuals develop ulcer disease and 1 to 2 percent

Fig 2 Map represents the global prevalence of H. pylori To display smaller countries, certain regions magnified [3]

are likely to develop gastric cancer. Furthermore, the severity and frequency of disease caused by H. pylori are governed by various host and environmental factors[64-66] (Figure 4).

roughly 6-20%. In western societies, the likelihood of developing gastric cancer during one's lifetime is around 1%-2%, while in Japan, it is 11%-12% or even higher A hypothesis suggests that being infected with H. pylori during childhood could raise the likelihood of developing stomach cancer at a later stage of life The study of Mongolian gerbils indicated that early infection with H. pylori was associated with a significant increase in susceptibility to gastric chemical carcinogenesis compared to late infection[10]

5.1 Anemia

The ability of H. pylori to maintain long-term colonization is an important factor in the development of diseases [34] The symptoms of acute H. pylori infection in adults usually include mild to moderate dyspepsia and occasional vomiting, which can begin a few days after infection, reach their maximum intensity during the second week, and then gradually decrease. The clinical course of chronic H. pylori infection can vary greatly and is influenced by factors such as the microbe itself, the host, and the environment. In almost all infected individuals, H. pylori causes chronic gastric mucosal inflammation [10]. Gastritis develops rapidly and persists following H. pylori infection. Along with its persistence, chronic gastritis may gradually transform into atrophic gastritis after several years of infection. To H. pylori-positive adults, atrophic gastritis is known to occur at a rate of 1-3% per year [68] Minorities of individuals infected with H .pylori develop severe gastroduodenal disease, such as Duodenal Ulcers (DU), gastric ulcers, and rarely gastric adenocarcinomas or mucosa-associated lymphomas (MALTs) [10] To individuals who are not infected with H. pylori, those who are infected have a 4-6 times higher chance of developing peptic ulcer disease. They also have a roughly 6 times higher chance of developing non-cardia gastric adenocarcinoma and gastric MALT lymphoma In people who are infected with H. pylori, the chances of developing peptic ulcers during their lifetime are

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Among the most important micronutrients for animals and microorganisms, iron serves as a cofactorforenzymesinvolvedinoxygenandelectron transport, as well as DNA synthesis. During infection, an iron retention mechanism reduces the redistribution of iron from the cell cytosol to the cell surface, as well as circulating transferrin and the growth of invading pathogens [69]. Kato et al demonstrate bacterial isolates from iron deficiency anemia patients, the SabA gene was highly expressed, suggesting that this virulence factor may contribute to anemia development [70]. Additionally, H. pylori cause hypochlorhydria and atrophic gastritis, as well as peptic ulcer disease and an increased risk of gastric cancers. In this instance, diminished iron absorption can result in iron deficiency anemia [71]. In patients with atrophic corpus gastroenteritis, intrinsic factor secretion is impaired, hypochlorhydria may occur, and iron and B12 may not be absorbed in the intestines as a result [72].

5.1 Gastric cancer

Despite a decline in incidence in high-income countries, gastric cancer is the second leading cause of cancer-related death globally [73] In 1994, the World Health Organization categorized H. pylori as a class 1 carcinogen due to its potential to cause cancer in humans [34] . Subsequent studies have confirmed the link between H. pylori infection and gastric cancer, attributing approximately 70% of 35 noncardia adenocarcinomas to H. pylori infection [74] However, a Few percentages of infected people develop stomach cancer [75] Individuals who have low levels of gastric acid secretion and corpuspredominant gastritis, a condition that results in

Fig 3 Schematic graph illustrating the factors that are responsible for gastric pathology and the subsequent disease consequences [67]

atrophic gastritis, loss of parietal cells, and subsequent hypochlorhydria, are more likely to develop gastric cancer [76] There are several postulated carcinogenic mechanisms, including inflammation-induced epithelial turnover In addition, hypertrophy and hypochlorhydria of the stomach can lead to impaired antioxidant absorption, infection with carcinogenic microbes, and the accumulation ofcarcinogeniccompounds in thebody [75]. Infection with H. pylori upregulates the proinflammatory cytokine IL-1, which is also a potent acid secretion inhibitor. Hypochlorhydria and cancer have been linked to polymorphisms believed to increase IL-1 activity, evidence supporting the role ofgastricacidityinthedevelopmentofcancer [77]

5.2 Gastritis

5.2.1 Acute gastritis

Significant inflammation of the distal and proximal stomach mucosa, momentary nonspecific dyspeptic symptoms, nausea, vomiting, and stomach fullness characterize an acute infection with H. pylori. On the basis of reports from patients who accidentally or deliberately consumed H. pylori or acquired infections through contaminated food or water, these symptomswereidentified. [78,79]

5.2.2 Chronic gastritis

Persistent infection of H. pylori in the human Gut correlates with the distribution of gastritis and the level of acid secretion (Figure 4). The acid secretion level has antagonistic effects on H pylori. In particular, H. pylori infects the gastric antrum, where a low acid-secretory layer of parietal cells exists. This infection is identified by a predominant antrumbased gastric inflammation. In patients with deficient acid secretion, bacteria are uniformly distributed within the corpus and antrum, as well as in close proximity to the gastric mucosa [80]. Persistent inflammation of the corpus mucosa promotes hypochlorhydria, in conjunction with local inflammatory factor responses such as interleukin1(IL-1), which then produces suppressive responses on parietal cell function, as evidenced by reports indicating that eradication therapy increases acid secretioninpatients [81] Furthermore,patients witha proinflammatory genotype are more likely to develop chronic gastritis, making them prone to

intestinal metaplasia, atrophic gastritis, and ultimatelygastriccancers [77]

5.3 Peptic ulcer disease

The revelation that H. pylori is the cause of peptic ulcer disease has resulted in a change in the treatment approach for patients with ulcers [82] Infected individuals face a lifetime risk of peptic ulcer ranging from 3% in the United States to 25% in Japan [83] H. pylori is believed to be the cause of 95% of DUs and 70% of gastric ulcers [84] H. pyloriinduced gastritis, diminished somatostatin levels, and increased gastrin and acid secretion are associated with duodenal ulcers [83] As a result of gastric metaplasia in the duodenum, additional bacterial colonization may occur, resulting in duodenitis and epithelial damage. Gastric ulcers are linked to corpus gastritis, which is believed to harm theepitheliallining [75]

5.4 MALT Lymphoma

Among digestive system marginal zone lymphomas, gastric MALT lymphoma (GML) is the most prevalent In accordance with epidemiological, pathological, clinical, and bacteriological evidence, the association between H. pylori and this lymphoma is now well established [85]. H. pylori eradication therapy is now regarded as the primary treatment for low-grade GML [86, 87]. After eradicating the bacteria with antibiotics, additional research has indeed revealed a regression of GML lesions. 60% to 90% of patients can experience lymphoma regression after H. pylori eradication [88]. The neoplastic cells of GML are already sensitized to the antigens of H. pylori if a reinfection occurs [89]. H. pylori infection was the first bacterial infection to be categorized as a type 1 carcinogen, the highest level, due to its link with gastric adenocarcinoma. It has been extensively studied since its discovery in order to identify virulence factors or genetic markers. but H. pylori strains associated with GML have received little attention. [88].

5.5 Non-ulcer dyspepsia

Non-ulcer dyspepsia (NUD) or functional dyspepsia refers to pain or discomfort in the upper gastrointestinal tract without any observable structural irregularities. The relationship between H. pylori infection and non-ulcer dyspepsia has been intensively studied. 30–60% of patients with

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dyspepsia will be infected with H. pylori. However, the rate of symptoms in the non-infected control group is also comparable [90]. Therefore, there has been considerable debate regarding the anticipated outcome of H. pylori eradication in dyspepsia patients. In a meta-analysis of non-ulcer dyspepsia (NUD), according to a study, eradicating H. pylori decreased the chance of experiencing dyspeptic symptoms by 8% when compared to a placebo. The study also found that eradicating H. pylori in 18 patients would be necessary to alleviate dyspeptic symptoms in one patient [91]. Nonetheless, in patients with functional dyspepsia, Maastricht IV guidelines now recommend eradication, particularly inregions witha highprevalence [87]

5.6

The immune system is activated by H. pylori infection, resulting in the production of inflammatory cytokines such as tumor necrosis factor (TNF-) as well as leptin and adipokines, which mount an immune response against the inflammation Studies have shown that low levels of leptin can cause insulin resistance (IR) due to elevated levels of TNF- and IL-6 [92] Inflammatory cytokines can have a substantial impact on insulin function by phosphorylating serine residues on insulin receptor substrates, which interferes with their interaction with insulin receptors Thus, diabetes can result from a breakdown in blood glucoseregulation[92].

VI. PATHOGENESIS OF H. PYLORI INFECTION

In the past, it was believed that the gastric environment was sterile due to its high acidity before Warren and Marshall discovered that H .pylori [93]. To achieve in challenging conditions, the bacterium employs several mechanisms to enhance its mobility, robust adhesion to epithelial cells, and use enzymes to establish an optimal microenvironment to sustain infection[94].

Figure 4 Aspects of H. pylori infection. CagA: Cytotoxin associated antigen A; VacA: Vacuolating cytotoxin; DupA: Duodenal ulcer promoting gene A protein; OipA: Outer inflammatory protein; GGT: Gamma-glutamyl transpeptidase; TLRs: Toll-like receptors[95]

In addition, the pathogenicity of this infection (GGT) can be attributed to various virulence factors, such as cytotoxin associated antigen A (CagA), vacuolating cytotoxin (VacA), duodenal ulcer-promoting gene A protein (DUPA protein), outer inflammatory protein (OipA), and gamma-glutamyl transpeptidase [96] Moreover, probably through a Th1-polarized response against the pathogen, the host immune system plays a crucial role in the infection's progression(Figure5) [95].

While most individuals with H. pylori infection do not exhibit any symptoms, such infections raise the likelihood of developing diseases like peptic ulcers andgastricadenocarcinomas [97].Inthisway, proper clinical management precedes an accurate diagnosis and is followed by effective treatment in order to improve a patient's clinical outcome [98] H .pylori has been detected using a variety of invasive and noninvasive diagnostic methods, and bacterial resistance is a significant obstacle to eradicating infection [99]. In this sense, in an effort to improve treatment outcomes, new therapy regimens and probiotic administration have been tried [100] Moreover, several researchers have focused their efforts on the development of vaccines against H. pylori infection.

6.1 Colonization

There are different factors that are critical during H. pylori colonization in the mucosa tissue of the stomach(Figure6)

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Insulin Resistance

6.1.1 Production of Urease

H. pylori is not an organism that prefers an acidic environment, and the production of urease enzyme is one of its signature strategies to neutralize the acidic environment of the gastric lumen. For successful colonization of the gastric mucosa, H. pylori requires the presence of urease and its activation [78]. It has been shown in the presence of urea, H. pylori can tolerate a pH as low as 2.5, whereas in its absence, it can tolerate a pH range between 8.0 and 4.0 [101]. It contains a cluster of seven genes that control and regulate the urease enzyme biosynthesis process [102], and it has a complex structure composed of twelvesubunitsofUreAandUreB.. [103]

H. pylori urease is a hydrolase enzyme that hydrolyses urea to CO2 and NH3. In contrast to ureases produced by other bacterial species, H. pylori urease has a Km value of 0.8 Mmol/L, which enables it to act on even minute amounts of urea (as low as 5 Mmol/L). Utilization of urea and production of NH3 generate acid-neutralizing capacity, which enables H. pylori to maintain the proper pH in its periplasm and microenvironment. Thus, regulation of the proton motive force [104] . This strategy of H. pylori to maintain a neutral pH intracellularly while the pH of the surrounding environment remains low is a peculiar characteristic of H. pylori. This is necessary for the survival of H. pylori in acidic gastric juice. Moreover, the generation of NH3 by the urease enzyme in non-acidic environments may raise the native pH above pH 7.0, which may explain why H. pylori does not colonize niches other than the Gut. Furthermore, it has been demonstrated H. pylori is intoleranttoalkalineconditions [105].

6.1.2 Response to the harsh environment in the stomach

Jones and Zamble conducted an experiment in which they simulated the acidic conditions of the human stomach by exposing H. pylori to an external pH of 2.0 and observed the impact of a decrease in cytosolic pH on the bacteria. As a result, nickel-responsive transcription factors (HpNikR) activated transcription of the ureA gene, demonstrating how these bacteria adapt to harsh acidic conditions [106] The data obtained allows for the correlation between the acid adaptation of H. pylori and nickel homeostasis to be made. The reduction in mucosal

bicarbonate secretion caused by H. pylori may protect the gastric barrier from acid-induced damage to the mucosa, plays a role in the development of duodenal ulcers [107]. Through the transforming growth factor beta (TGF)-mediated p38 mitogen-activated protein kinase (MAPK) signaling pathway, H. pylori downregulate the expression of two transporters of cellular bicarbonate in the duodenal epithelium: (a) the cystic fibrosis transmembrane conductance regulator (CFTR) and (b) the solute linked carrier 26 gene family A6 (ALC26A6) [107] In a comparative transcriptomic analysis, Hathroubi et al discovered that 8% of the genes examined exhibited differences between H. pylori biofilm cells and planktonic cells The biofilm-downregulated genes were involved in metabolism and translation, while Biofilmupregulated genes encode proteins involved in stress response and flagellum formation [108]. Potentially promoting the persistence of H. pylori in the stomach, thisbiofilmformation.

6.2 Virulence factors

6.2.1 Outer membrane vesicles

virulence factors of H. pylori can be present in a solubleform,attachedtothecellsurface,ordelivered into host cells through the host's type IV secretion system (T4SS). Recently, there is a proposed significant function of outer membrane vesicles (OMVs)producedby H. pylori inthedisseminationof bacterial antigens. OMVs contain a variety of

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Fig 5 Colonization strategies and establishment of gastric mucosal infection by H. pylori [109].

biologically active compounds produced by H. pylori, are capable of being internalized into host cells, and as a consequence, in addition to influencing signaling pathways, they can promote the apoptosis of gastric epithelial cells as well as immune cells This can have the effect of either enhancing or suppressing immune responses, resulting in the eventual onset of a disease [110] Through the utilization of protonography and mass spectrometry, Ronci et al. confirmed the existence of -carbonic anhydrase (CA) in OMVs produced by H. pylori strains with planktonic and biofilm characteristics. This work suggested that CA, along with urease, may have a crucial role in reducing the acidity of gastric juice caused by H pylori [111] The protein composition, immunogenicity, and method of entry into host cells of OMVs are influenced by their size. OMVs with sizes ranging from 20-100 nm can enter host cells via caveolin-dependent endocytosis, while OMVs with sizes of 90-150 nm can enter through macropinocytosis and endocytosis. These results indicate the importance of OMVs in the pathogenesis of H pylori and the possible use of OMVs in the developmentofvaccines [112]

6.2.2 CagA

It is a bacterial protein called CagA, which induces changes in morphology, alters their polarity, and causes hummingbird-like phenotypes in epithelial cells This virulence factor can also trigger changes in the cytoskeleton associated with gastric adenocarcinoma development [113]. In addition to the CagA gene, the cag pathogenicity island also contains the code for a type IV secretion system (T4SS) [114]. CagA and peptidoglycans are translocated into host cells by this bacterial structure [115]. In the host cell, CagA is tyrosine phosphorylated at the Glu-Pro-Ile-Tyr-Ala (EPIYA) motif, which consists of different EPIYA segments (EPIYA-A, EPIYA-B, EPIYA-C, and EPIYA-D) in the variable C-terminal region of the protein [116]. While EPIYA-A and EPIYA-B segments are found in most cagA-positive H. pylori strains, the EPIYA-C and EPIYA-D segments are linked to Western and Eastern strains, respectively [117] Strains of H. pylori with EPIYA-D or at least two EPIYA-C segments in their cagA gene are related with an increased risk of cancer [118] Moreover, research on a Brazilian population has revealed that relatives of individuals

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with gastric cancerare morelikelytobe infected with H. pylori strains containing two or more EPIYA-C segments [119] CagA is activated by phosphorylation, resulting in the activation of SHP-2 (SH2-containing protein-tyrosine phosphatase), which promotes the changes described above in the cell[120]

6.2.3 Non-CagA virulence factors

Several virulence factors have been associated with an increased ability of H. pylori to impair gastric homeostasis Among them, VacA gene is present in almost all strains of bacteria, including H. Pylori, and is a determinant of the pathogenicity of this bacterium VacA induces the creation of acidic vacuoles within the cytoplasm of gastric epithelial cells This results in the destabilization of mitochondria, cytoplasmic membranes, and endomembranous structures, leading to the collapse of cells [121] Additionally, this protein may also be responsible for activating and suppressing the immune response, resulting in immunity tolerance and persistent infection with H pylori through interactions with T-cells and antigen-presenting cells [122]. This virulence factor is responsible for a series of alterations that contribute to increased gastritis, as well as the development of ulcers and cancer [123]. Another bacterial protein known as DupA appears to give the bacterium with a higher level of acid tolerance. It also has the potential to stimulate an increase in the synthesis of IL-8 in the mucosa of the antral gastric region. Elevated levels of IL-8 result in mucosal inflammation and the influx of polymorphonuclear leukocytes, potentially causing gastritis and duodenal ulcers [124]. Notably, a link between dupA-positive H. pylori strains and duodenal ulcers has been established in Asian countries, but not in Western countries [125]. Furthermore, the research has shown that the presence of functional dupA in H. pylori strains should be considered a protective factor against the development of gastric cancer. [126]. The gene products of dupA show similarity to the VirB4 ATPase, which plays a role in the construction of the secretion machinery. Nonetheless, the precise connectionbetweendupA and H. pylori T4SSremains to be elucidated [124]. OipA, an outer membrane protein contributes to adhesion and inflammation by stimulating the production of IL-8. The increased

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number of investigations on this H. pylori virulence factor stemmed from the identification of the link between OipA and the increased incidence of peptic ulcers and gastric cancer [127]. Since the expression of the oipA gene is regulated by a repair process called "slipped strand mispairing," whichdepends on the quantity of CT dinucleotide repeats in the oipA 5' region, the functional status of OipA has been described as an important factor in the outcome of the infection. This is because the expression of the oipA gene is regulated by a repair process called "slipped strand mispairing.". This process determines whether oipA in a specific bacterial strain is nonfunctional or functional, and the latter condition is associated with higher stomach pathogenicity [128] Furthermore, it is plausible that OipA is linked to modifications in -catenin signaling, reduction in cell-cell junctions, and enhanced cell proliferation [129] H. pylori produces GGT, which is an enzyme with N-terminal nucleophile hydrolase activity. GGT can facilitate the conversion of glutamine into glutamate and ammonia, and also catalyzes the hydrolysis of glutathione into glutamate and cysteinylglycine [96]. As a result of its activity, reactive oxygen species (ROS) are produced, which, like ammonia, cause cell cycle arrest, apoptosis, and necrosis [130]. In addition, according to scientific investigations, this enzyme inhibit T cell proliferation and dendritic cell differentiation. [131]. Patients with peptic ulcers have been found to have a greater GGT activity than those with other gastroduodenal disorders[132].

6.3 Immunologic aspects

H. pylori infection induces complex immune responses, including innate and adaptive responses [133]. Considering the initial exposure to the pathogen, various H. pylori antigens such as lipoteichoic acid, lipoproteins, lipopolysaccharide, HSP-60, NapA, DNA, and RNA bind to gastric cell receptors, including toll-like receptor (TLR) 1, TLR2, TLR4, TLR5, TLR6, and TLR10 located on epithelial cell membranes, and TLR9, found in intracellular vesicles [134]. This connection stimulates, among other signaling pathways, the activation of NF-B and c-jun N-terminal kinase, followed by the release of proinflammatory cytokines [135]. The injection of CagA through T4SS does not only activate receptors by pathogen-associated molecular patterns, but also

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induces the production of cytokines, a process that is dependent on the NF-B pathway [136]. Subsequently Neutrophils and mononuclear cells infiltrate the stomach mucosa, leading in the generation of nitric oxide and reactive oxygen species [137] In addition, adaptive immunity's components, namely CD4+ and CD8+ T cells, are also brought in. There may be a preferential activation of CD4+ cells over CD8+ cells, and a particular response is focused toward the bacterium [138] Studies suggest that in H. pyloripositive patients, there is a Th1-polarized response in terms of cytokine profiles, characterized by decreased levels of the Th2 cytokine IL-4 and increased levels of gamma interferon, tumor necrosis factor, IL-1, IL-6, IL-7, IL-8, IL-10, and IL-18 [139] Apart from IL-10, which appears to have a function in controlling the inflammatory response, the other cytokines that are elevated may contribute to the proinflammatory effects that occur during infection with H. pylori Additionally, it is shown that an increase in IL-17 is associated with H. pylori infection, especially in adults [140]. The presence of H pylorispecific serum IgM antibodies in patient serum can be detected 4 weeks after infection when it comes to the production of immunoglobulins [141] During chronic infection, a variety of bacterial antigens are targeted by IgA and IgG immunoglobulins in the bloodstream [95] . The majority of H. pylori-positive individuals do not experience symptoms of this inflammation, however, it increases their risk of developing duodenal and gastric ulcers as well as stomachcancerinthelong run [83].

VII. DIAGNOSTIC TESTS FOR DETECTION OF H. PYLORI INFECTION

Infection with H. pylori is detectable by both invasive and non-invasive diagnostics. The technique chosen depends on the patient's requirements. Several factors need to be taken into account, such as the existence of warning signs, the application of nonsteroidal anti-inflammatory drugs (NSAIDs), and being elderly (either over 45-50 years old or over 60 years old)[142], history of premalignant symptoms or surveillance for a past malignancy mandates an upper endoscopic assessment. Doctors can utilize esophagogastric-duodenoscopy to visually inspect the mucosa, take biopsy samples for histological analysis, urease testing, bacterial culture, and,

Aljaberi etal./CurrentUnderstanding oftheTransmission,Diagnosis,andTreatment of H.pyloriInfection: A ComprehensiveReview

potentially, molecular testing. In the absence of an endoscopic suggestion, non-invasive diagnostics, such as urea breath testing or stool antigen assay, can beusedto confirmthepresenceofanactive infection. In certain circumstances, a physician may employ serology as a diagnostic tool to assist in the identification of bacterial infections [143]. However,

the diagnostic approach can't be independent of the availability of the test in the patient's area, how much it will cost, or what the patient wants. Wang et al. briefly review the current options and advances of diagnostic tests and their associated clinical applications, as well as the selection of diagnostic testsforvariousclinicalsituations(Table3) [144]

Table 2 Diagnostic options for H. pylori infection in various clinical settings and specific diagnostic test applications [144].* Although serology is unaffected by local changes in the stomach, it should be evaluated with caution prior to further management

7.1 Non-Invasive Tests:

Non-invasive test can detect the active infection or provide withinformationa previousinfection.

7.1.1 Urea breath test

The diagnosis of H. pylori can be done non-invasively through UBT. Based on a basic premise, to perform UBT,patientsingesturea thathasbeentagged with 13 C or 14 C. H. pylori produces the enzyme urease, which breaks down the urea into ammonia and 13 Clabeled carbon dioxides. This 13 C carbon dioxide then enters the bloodstream, travels to the lungs, and is eliminated through exhalation [145]. Typically, it is administered in combination with citrus juices, such aslemon ororange, topostponetheprocess ofgastric emptying and enhance the duration of contact with the mucosal lining. After drinking the test solution, the exhaled air is collected in a sealed plastic bag 30 minutes later. Air sample analysis can be performed using either a mass spectrometer or infrared spectroscopy. The latter is considered a more straightforward and cost-efficient alternative to mass

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spectrometry. Infrared spectroscopy is the method of choice for determining the 13C/12C isotope ratio. The increase in labeled CO2 is expressed as a delta value compared to the baseline (DOB). The DOB measurement is directly associated with the bacterial load of H. pylori, meaning a higher DOB value indicates a higher bacterial load. Thus, based on the presence of 13C in exhaled air, we can detect with great accuracy whether a patient is infected with H. pylori, and based on the value of the 13C/12C ratio, we can evaluate the severity of infection. It is similar to the 14C urea breath test, except that 13C is not a radioactive isotope. The typical urea breath test contains 75 mg of 13C. 13C-UBT has a sensitivity of 96–100% and a specificity of 93–100% [145, 146]. The BREATH QUALITY UBT could be decreased to 15 minutes, according to one study, without compromising the method's accuracy [147] The meta-analysis conducted showed that the test is highly accurate in children of any age. For children older than 6 years old, sensitivity was 96.6% and

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specificity was 97.7%, respectively; for children younger than 6 years old, sensitivity was 95% and specificity was 93.5%. [148]. Recently, a new UBT approach employing a tablet formulation of 13C-urea has been proposed. This technique provides for highly accurate breath sampling within 10 minutes after ingesting a tablet. Using tablets has a benefit of preventing the interaction between the ureaseproducing bacteria in the oropharynx and the formulation, which could cause inaccurate positive results. This is one of the benefits of taking the medication in this form [149, 150] Although rare, false-positive outcomes can occur in patients who have undergone gastric resection or have experienced a significant reduction in stomach output, especially when endoscopy with biopsy has been performed shortly before the test The primary cause of false-positive results is typically the breakdown of urea by bacteria that possess urease in the oral cavity or the stomach [151]. This is especially common when achlorhydria or hypochlorhydria is present. A few instances of false-negative outcomes could beduetoerrorsinthemethod ofcollectingand storing exhaled air samples, or from physical exertion before or during the test. As with most other tests, a reliable UBT result may be obtained after discontinuing PPIs for a period of two weeks, and no earlier than four weeks after stopping antibiotics and bismuth[145]

7.1.2 Stool Antigen Test

Tests that are easy to perform and designed to identify H. pylori antigen in stool samples have been shown to have a high level of accuracy in extensive comparisons with identical tests [152]. In general, stool monoclonal antibody tests are more precise than stool polyclonal antibody tests, with a combined sensitivity of 93% and specificity of 96% [153]. They also demonstrated a high level of diagnostic accuracy in pediatric settings, particularly when tests were based on ELISA rather than immunochromatography [154]. In a Houston Consensus Conference, a group of 11 experts recommended using stool antigen testing (or UBT) for the initial diagnosis of H. pylori infection and post-treatment (when endoscopy is not required) [142]. The UBT and the stool antigen test both have the advantage of being able to evaluate the entirety of the stomach's contents, in contrast to the histology and RUT, which can only evaluate a small

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portion of a biopsy specimen. Both stool antigen tests and UBT are the most reliable methods of diagnosing an active infection with H pylori, both theoretically and practically Nevertheless, any drug that lowers H. pylori numbers below the threshold of detection may result in false negative results, especially when used in conjunction with a proton pump inhibitor, bismuth-containingcompound,orantibiotic [155]

7.1.3 Serology

A systemic immune response is brought on by H. pylori infection of the stomach. Antibodies to H. pylori can be detected in the blood anywhere from three to four weeks after infection. The presence of these antibodies can be ascertained using any one of the following three techniques: an enzyme-linked immunosorbent assay (ELISA), a latex agglutination test, or a Western blotting analysis. Among these, the ELISA test is the one that is used most frequently [156] Detection of IgG, IgA, and IgM antibodies in the bloodstream is the basis of this technique Since H pylori is a chronic infection, only a validated IgG test can be used to detect it [157]. There are a number of serologic tests available for the diagnosis of H pylori; they can be performed non-invasively, and quickly, no special equipment is required, and can be used to screen large populations for the presence of the infection. However, Serology may be positive as a result of a current infection at the time of the test, a past infection, or cross-reacting non-specific antibodies [158].The production of immunoglobulins (antibodies) against antigens is triggered by active infection, previously acquired infection, or nonspecific cross-reacting antibodies [156]. Serological tests are therefore able to be used for both the initial diagnosis and confirmation of H. pylori infection. Serological tests should not be used for therapeutic follow-up after successful eradication because the level of quantitative antibodies after successful eradication, the population does not decline significantly for a long time. Moreover, false-positive serologic results are common in populations with a low prevalence (40%) of H pylori infection, since the positive predictive value of serology is dependent on the prevalence of H pylori infection in the population [159] Serology is not recommended in such populations, and if a serological test of H. pylori is positive, further confirmation is necessary, such as a biopsy culture, urea breath test, or stool antigen test.

Recent The use of proton-pump inhibitors, antibiotics, bismuth preparations, gastrointestinal hemorrhaging, or atrophy of the gastric mucosa does not affect the serological results [157] Serological tests vary in their specificity and sensitivity. The test's sensitivity and specificity were 85% and 79%, respectively, according to a meta-analysis. According to another study, the range of sensitivity was 76% to 84% and the range of specificity was 79% to 90% [159] Several investigations have shown that elevated levels of anti-H. Pylori IgG antibodies are linked to the severity of histological gastritis, the density of bacteria in the mucosal lining, and the presence of blood biomarkers for stomach function, such as PGI, PGII, PGI/II ratio, and gastrin-17. However, there have been other studies with contradictory findings, making the results inconclusive [160]

7.2 Invasive Tests: 7.2.1 Histology

By analyzing biopsy samples of stomach mucosa, it is possible to detect H. pylori with a sensitivity of 95% and a specificity of 98%. In addition, it makes it possible to visualize the morphology of the stomach at any time. To achieve a precise diagnosis, two antral biopsies must be performed, one from the gastric angulus and two from the corpus [161]. For example, when biopsy samples were not obtained from the angulus in 213 patients, 8% and 3% of cases of atrophic gastritis and intestinal metaplasia were missed, respectively [162] There is some concern that the widespread use of proton pump inhibitors (PPIs) may lead to the development of an atypical gastritis or bacterial density changes at several sites in the body as a result of the use of these medications [163] H. pylori infections can be accurately diagnosed histologicallyby utilizinguniquestainingtechniques, immune stains, or digital pathology [164, 165]. However, according to a recent study, standard hematoxylin-eosin staining was able to detect 94% of H pylori, while special staining did not show the same levelofdetection. [166].

7.2.2 Rapid Urease test

Upper endoscopy enables the collection of biopsy specimens for urease testing. The approach takes advantage of the organism's pre-formed urease; in solutions containing urea, the enzyme releases

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ammonia, resulting in an increase in pH and a color change in the medium. The rapid urease test (RUT) is a quick, simple, cost-effective, and very specific method of diagnosing H. pylori infection. However, in order to perform RUT, a high density of bacteria is necessary. For instance, in the normal commercial kits at least 104 bacteria must be present in the stomach specimen [167] It is possible to obtain false negatives if you have recently taken antibiotics, bismuth-containing compounds, or PPIs, especially omeprazole and lansoprazole, or if your child is younger than five years of age [168]. It has been demonstrated that obtaining biopsies from the corpus, as opposed to the antrum, or mixing antral and corpus samples, increases RUT sensitivity [169, 170] In contrast, Dechant et al. found that the rapid urease test (RUT) is more effective than histology in detecting H. pylori infection in patients who have undergonetreatmentwith PPIsorantibiotics [171]

7.2.3 Culture

As well as performing histological examinations and RUTs, upper endoscopy can be employed to collect gastric specimens in order to conduct bacterial culture, susceptibility testing, and, ultimately, organism genotyping. Although culture has a high specificity, low sensitivity, because H. pylori are difficult to grow, and requires the expertise of a laboratory. Using a preheated 35Co blood agar and transporting the material to the laboratory within 30 minutes of collection can improve sensitivity (BD Diagnostics, Sparks, MD, USA) and a helicobacter selective agar, containing polymyxin (HyLaboratories, Rehovot, Israel) and the antibiotics colistin. An alternative strategy to consider is to culture the specimens under microaerophilic conditions (using CampyGenTM, Oxoid, Hampshire, UK) at 35°C for an extended period of 14 days, or to modify the atmosphere by adding hydrogen, or by treatingthespecimens with trypsin[172,173].

7.2.4 Endoscopy

The development of high-resolution endoscopic technology has made it possible to increase diagnostic accuracy in the process of identifying H. pylori infection and the lesions that are associated with it. Advanced imaging methods with the highest resolution include high-resolution microendoscopy, optical coherence tomography, endocytoscopy, and

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confocal laser endoscopy [174, 175]. At present, none of these techniques allow for "optical biopsies" to be widely available or specific enough to allow for a real-time diagnosis of H. pylori infection. A study involving 300 patients in Japan showed that the conventional narrow-band imaging (NBI) technique is strongly associated with the histopathologic severity of H. pylori gastritis The NBI mucosal patterns showed five different degrees of H. pylori gastritis (gastric atrophy, inflammatory infiltration, and H. pylori density) [176] . Kawamura et al [177] indicated endoscopic magnifying technique using NBI demonstrated micromorphological differences that correlated with histological findings among individuals with distinct H.pylori-related diseases Confocal laser endomicroscopy is a functional imaging method that can be used to identify abnormalities in the mucosal barrier in patients with H. pylori infection and IM [178] Moreover, a new endoscopic imaging technique called endocytoscopy, in vivo histology and guided biopsies can be obtained accurately and safely using this approach Endocytoscopy permits microscopic imaging at a 1,400-fold magnification, it allows for cellular examination of mucosal structures and detection of H .pylori in vivo [179].The current development of functional and molecular-targeted imaging technologies may be useful in diagnosing H. pylori infectionsinreal-time[180]

7.3 Molecular test

Molecular methods, such as polymerase chain reaction (PCR), have increasingly been used to detect and type H. pylori and related species, as well as determine how susceptible these bacteria are to antibiotics in recent years. Kalach et al [181], as a result of the study, they concluded that quantitative real-time PCR (qPCR) in detecting H. pylori infections in gastric biopsies of French children, it is more precise than routine culture, histology, or RUT alone. It permits the detection of low bacterial loads. It has been demonstrated that quantitative PCRs and nested PCR techniques can detect H. pylori in specimens such as inflammatory tooth pulp, saliva, and dental plaque in the oral cavity [182, 183] Comparatively to conventional methods, a novel method for detecting 16S rRNA and ureC genes of H pylori using the GenomeLabTM Genetic Analysis System (Beckman Coulter) has demonstrated high

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performance [184]. Paraffin and formaldehyde used for tissue preservation may reduce the efficiency of subsequent molecular amplification of microbial DNA. Rabelo-Goncalves et al [185] A study compared the efficacy of five different commercial DNA extraction methods and the phenol-chloroform method for detecting H. pylori using PCR amplification of the 16S rRNA gene in liver tissue that had been formalin-fixed and paraffin-embedded Although samples extracted with phenol–chloroform included the highest proportion of positive cases (70%), there was no statistically significant difference between the techniques. Infections caused by H. pylori are being treated with omics-based methods. Kim et al [186] through pyrosequencing 16S rDNA amplicons of gastric biopsy specimens, H. pylori was detected in all samples suspected to be positive for H. pylori, as well as, shockingly, in sixty percent of the samples that were thought to be negative for H. pylori. In one work, SOLiD sequencing was done on two H. suis genomes in order to generate appropriate PCR primers. The researchers were successful in finding H. suis DNA in gastric biopsy specimens taken from mice that had been experimentally infected [187] Electrophoresis was performed using two-dimensional (2D) gels [188] to compare the cellular proteomes of H. pylori with non-pylori Helicobacter species, including Helicobacter mustelae, Helicobacter felis, Helicobacter cinaedi, Helicobacter hepaticus, Helicobacter fennelliae, Helicobacter bilis, and Helicobacter cholecystus It was feasible to differentiate between stomach and enterohepatic Helicobacter species on the basis of their characteristic 2D protein profiles. In order to detect the presence of levofloxacin resistance directly in gastric biopsy samples, Trespalacios et al. developed novel primers for the identification of the N87I mutation in the gyrA gene of H. pylori The application of the new primers resulted in an increase in the sensitivity of the approach for predicting levofloxacin resistance from 52 to 100 [189] The efficacy of the GenoType HelicoDR kit for the rapid detection of the A2143G mutation in the 23S rRNA gene associated with clarithromycin resistance and the N87K mutation linked to fluoroquinoloneresistance wasevaluated in 42 H. pylori isolates.Comparedtosequencing,thetest demonstrated a sensitivity and specificity of over 80% for the identification of clarithromycin and fluoroquinolone resistance.; however, compared to

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MIC results, it demonstrated a sensitivity of 55% for detectingclarithromycinresistance [190]

VIII. TREATMENT OF H. PYLORI INFECTION

The Maastricht V/Florence Consensus Report, a brand-new European standard for treating H pylori infection, suggests the following treatment plan (Figure 7) [191]. At first, when there is less than 15% of a region's population that is resistant to clarithromycin, the conventional triple regimen of proton pump inhibitors (PPI), amoxicillin, and clarithromycin is advised. According to Murakami et al., the standard triple regimen (Lansoprazole 30 mg bi-day, 750 mg bi-day amoxicillin, and 400 or 800 mg bi-day clarithromycin for 7 days) obtained a 97.3% success rate in the elimination of the strains that are sensitive to clarithromycin [192]. As a first-line treatment for clarithromycin-resistant infections, bismuth-containing quadruple therapy is recommended for areas with a high level of resistance (> 15%) to clarithromycin. An alternative treatment option is non-bismuth quadruple concomitant therapy (metronidazole , amoxicillin, clarithromycin, and PPI) in regions in which clarithromycin resistance is high, but metronidazole resistance is low to intermediate [191, 193]. When clarithromycin and metronidazole face significant resistance in a particular region, the recommended primary treatment option is bismuth-containing quadruple therapy. In China, patients diagnosed with H. pylori-induced chronic gastritis have a higher success rate with first-line therapy consisting of ten daysofbismuthquadruple therapyas opposedto ten days of normal triple therapy (86.1% vs. 58.4%, ITT analysis) [194] If both the initial treatment (triple or non-bismuth quadruple therapy) and the second treatment (quinolone-containing therapy) fail, then the appropriate course of action is to use quadruple therapy that includes bismuth. In France, 83% of individuals treated with bismuth-containing triple therapyweresuccessfullyeradicated [195]

It is recommended that after the failure of first-line therapy with bismuth quadruple and second-line therapy with quinolones, triple or quadruple therapy with quinolones be used [191] In areas where clarithromycin resistance is high but metronidazole resistance is low or moderate, the triple therapy

(which includes amoxicillin, metronidazole, and PPI) may be a useful alternative if metronidazole was not initially used as a treatment [196] The third- and fourth-line therapy reports are detailed in Tables 1, 2, and 3. Quinolone-based treatment is one of the most prevalent third-line regimens. Levofloxacin has been frequently utilized as an H. pylori rescue medication [197-199]. However, the efficiency of levofloxacinbased therapy against gyrA mutation-positive bacteria is insufficient; approximately 40% eradication rates are seen [200]. As a result of using a sitafloxacin-containing treatment, up to 70% of gyrA mutation-positive strains were able to be eradicated successfully [201, 202]. A randomized trial demonstrated that the eradication rate of triple regimens including sitafloxacin was superior to that of triple regimens containing levofloxacin [203] Therefore, currently, if available, sitafloxacin is the most effective fluoroquinolone. However, quinolone resistanceiseasily acquired,andsome strainsacquire double mutations in gyrA that confer a high level of resistance [204]. In contrast, it has been reported that rifabutin-containing medication is a third-line treatment [205]. Due to the rarity of rifabutin resistance, H. pylori strains resistant to numerous antibiotics can be defeated by rifabutin-containing therapy. However, Rifabutin-containing therapy should be used with caution due to side effects such as leukopenia and thrombocytopenia, as well as the occurrence of multi-resistant strains of Mycobacterium tuberculosis [206]. In terms of the duration of rifabutin-containing therapy, 10-day or longer therapy was superior to 7-day therapy [206, 207]. An eradication rate of 83.3% was reported for 10-day regimens containing rifabutin and 94.1% for 14-day regimens [207]. In terms of PPI dosage, rifabutin therapies with high dose PPI achieved more effective eradication than standard PPI dosage [208]. The presence of bismuth had an additional effect on the metabolism of rifabutin-containing regimens. Contrary to what most people believe, the use of high-dose PPI and amoxicillin as a third-line treatment regimen can be a useful alternative [209211]. Rabeprazole (10 mg qid) and amoxicillin (500 mg qid) for 14 days were previously reported to have an eradication rate of 63.0% [209] There is no significant difference between the eradication rates achieved with quinolone- or rifabutin-containing

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therapies; however, there are fewer worries about some problems and the development of new drug resistance with high-dose PPI and amoxicillin combination therapy. Vonoprazan, a the first-of-itskind potassium-competitive acid blocker with a potent effect on inhibiting stomach acid secretion, is highlighted. There was a clear improvement in the efficacy of the vonoprazan, amoxicillin, and clarithromycin triple regimen when compared with the standard lansoprazole, amoxicillin, and clarithromycin triple regimen (82.0 vs. 40.0%) for eradicating clarithromycin-resistant strains [192] There are only limited reports of vonoprazancontaining regimens that exclusively use a triple therapy approach [212] Therefore, it is recommended to consider alternative regimens that include vonoprazan, such as bismuth-quadruple therapyorconcomitanttherapy.

IX. RECURRENCE OF INFECTION

Recrudescence and reinfection are thought to be the mechanisms behind the recurrence of H pylori Recrudescence is not a sign of successful eradication but rather the return of the original strain of H. pylori after a brief suppression. Instead, genuine reinfection happens when a patient contracts the original strain of H. pylori or a different strain after eradication is complete [213] There has been evidence that late recurrenceisresponsibleforthehigh recurrencerates during the first three to twelve months after cure. A verified absence of H. pylori for a year following therapy is a credible sign of eradication effectiveness without recrudescence. It appears that low-efficacy

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medication merely temporarily suppresses the H. pylori infection in the gastric mucosa rather than curing it or removing it entirely from the host [214, 215] The recurrence of H. Pylori infection after successful eradication is one of the most challenging aspects of its management. Most recurring cases are presumably caused by recrudescence rather than reinfection because the frequency of recurrences declines over time, dropping off dramatically after the first year, and identified strains (before and after therapy) are typically genetically identical. In adults, reported "real" reinfection rates typically ranged from 0 to 23.4%. There were significantly lower annual "real" reinfection rates within the first year of eradication than reported annual recurrence rates within those first few years following eradication [213] H. pylori reinfection may also be caused through intrafamilial transmission; the presence of this organism in asymptomatic family members may encourage transmission between households [216]. In developed countries like Europe and the USA, the rate of H. pylori reinfection following eradication medication is incredibly low. Zendehdel et al. reported an annual reinfection rate of approximately 1% [215] Contrary to western populations, which have reported low rates of H pylori reinfection, developing countries have reported high rates of recurrence [217, 218]. Therefore, Due to the increased danger of re-exposure, it's possible that the high frequencyof H. pylori infection islinkedtoa high rate of infection recurrence following eradication [12]. Genetic factors may also be at play; those who have successfully eradicated H. pylori may still be susceptible to reinfection when exposed to H. pyloripositive individuals [216]. There have been a number of publications written about the occupational risk of H. pylori infection. Matysiak-Budnik [219] demonstrated a link between work exposure and a higher risk of infection. Williams [220], too, said that endoscopicstaffmembershavehigher jobrisk.

X. CONCLUSION

H. pylori infection is a major public health concern with significant morbidity and mortality worldwide. In this comprehensive review, we have highlighted the current understanding of the transmission, diagnosis, and treatment of H. pylori infection. The risk factors and epidemiology of H. pylori infection

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Fig.6 The Maastricht V/Florence Consensus Reportaligned treatment strategy for H. pylori infection is presented. [191].

have been discussed, along with the clinical manifestations and pathogenesis of the infection. Diagnostic tests for detection of H. pylori infection have been described, along with the various treatment options available for H. pylori infection. Although significant progress has been made in our understanding of H. pylori infection, challenges remain, particularly in the areas of antibiotic resistance and the development of effective treatments. In addition, the role of H. pylori infection in the development of extra-gastric diseases, such as cardiovascular disease and diabetes, remains an active area of research. In conclusion, continued efforts are needed to improve the diagnosis, treatment, and prevention of H. pylori infection. These efforts will require collaboration among researchers, clinicians, public health officials, and policymakers. By working together, we can reduce the burden of H. pylori infection and its associated complications, and improve the health outcomes of individualsaffected by this infection.

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